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Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

机译:抑制谷氨酸羧肽酶II(GCPII)活性作为多发性硬化症认知障碍的治疗方法

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摘要

Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that /V-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.
机译:在所有多发性硬化症(MS)患者中,有一半经历了认知障碍,因此没有药物治疗。使用磁共振波谱(MRS),我们检查了MS患者海马的代谢变化,将其发现与神经认知测试电池的性能进行了比较,发现/ V-乙酰基天冬氨酰胺(NAAG)浓度与认知功能相关。具体来说,患有认知障碍的MS患者海马NAAG水平较低,而具有正常认知能力的MS患者水平较高。然后,我们在MS实验性自身免疫性脑脊髓炎(EAE)模型中的认知度基础上评估了已知会增加脑NAAG水平的谷氨酸羧肽酶II(GCPII)抑制剂。尽管GCPII抑制剂的使用不会影响身体残疾,但与用载体治疗的EAE小鼠相比,它可以增加大脑的NAAG水平并显着改善学习和记忆测试的性能。这些数据表明,NAAG是MS认知功能的独特生物标志物,抑制GCPII可能是恢复认知功能的独特治疗策略。

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  • 作者单位

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287;

    Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287;

    Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Biostatistics, and Johns Hopkins University, Baltimore, MD 21287;

    Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Biostatistics, and Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287,Department of Radiology, Johns Hopkins University, Baltimore, MD 21287;

    Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287;

    Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287,Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Radiology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287,Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287,Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

    Department of Psychiatry and Behavioral Sciences,Johns Hopkins University, Baltimore, MD 21287,Department of Neurology, Johns Hopkins University, Baltimore, MD 21287;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    neuroradiology; hippocampus; 2-(phosphonomethyl)pentanedioic acid (2-PMPA);

    机译:神经放射学海马2-(膦酰基甲基)戊二酸(2-PMPA);

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